Smooth muscle proliferation has been implicated as a critical event in the development of stenosis following vascular reconstruction (e.g. percutaneous translumenal angioplasty), transplantation arteriosclerosis, and atherosclerosis (Ross, R. Nature 1993, 362, 801; Clowes, A. W.; Reidy, M. A. J. Vasc. Surg 1991, 13, 885). Pharmacological approaches to SMC proliferation inhibitors for the treatment of these states have included heparin and its fragments, (Castellot, J. J. Jr.; Wright, T. C.; Karnovsky, M. J. Seminars in Thrombosis and Hemostasis 1987, 13, 489), low molecular weight heparins (Tiozzo, R.; Cingi, M. R.; Tietrangelo, A.; Albcrtazzi, L.; Calandra, S.; Milani, M. R. Arzneim-Forsch./Drug Res. 1989, 39, 15), and heparin-mimicking agents (hepariniods) such as pentosan polysulfate, and fucoidan (Paul, R.; Herbert, J. M.; Maffrand, J. P.; Lansen, J.; Modat, G.; Pereillo, J. M.; Gordon, J. L. Thrombosis Research 1987, 46, 793; McCaffrey, T. A.; Falcone, D. J.; Borth, W.; Brayton, C. F.; Weskler, B. B. Biochem. Biophys. Res. Commun. 1992, 184, 773). However, many heparinoids, like heparin and heparin fragments, are heterogeneous, polymeric, highly anionic polysaccharides, most of which still retain significant anticoagulant activity (Maffrand, J. P.; Herbert, M. M.; Bernat, A.; Defreyn, G.; Delevassee, D.; Savi, P.; Pinot, J. J.; Sampol, J. Seminars in Thrombosis and Hernostasis 1991, 17 (Suppl. 2), 186; Boisson-Vidal, C; Colliec-Jouault, S.; Fisher, A. M.; Tapon-Bretaudiere, J.; Sternberg, C.; Durand, P.; Jozefonvicz, J. Drugs of the Furture 1991, 16, 539; Colliec, S.; Fischer, A. M.; Tapon-Bretaudiere, J.; Boisson, C.; Durand, P.; Jozefonvicz, J. Thrombosis Research 1991, 64, 143). SMC antiproliferative polyanionic compounds which possess well defined structure would not only be homogeneous in composition but would also be expected to inhibit smooth muscle proliferation without the liabilities, such as anticoagulant effects, associated with heparin and heparinoids.
Beta-Cyclodextrin tetradecasulfate has been described as a smooth muscle cell proliferation inhibitor and as an effective inhibitor of restenosis (Weisz, P. B.; Hermann, H. C.; Joullie, M. M.; Kumor, K.; Levine, E. M.; Macarak, E. J.; Weiner, D. B. Angiogenesis: Key Principle-Science-Technology-Medicine- Steiner R., Weisz, P. B.; Langer, R. Eds. Birkhauser Verlag, Basel Switzerland, 1992, pg. 107; Hermann, H. C.; Okada, S. S.; Hozakowska, E.; LeVeen, R. F.; Golden, M. A.; Tomaszewski J. E.; Weisz, P. B.; Barnathan E. S. Arteriosclerosis and Thrombosis 1993, 13,924; Reilly, C. F.; Fujita, T.; McFall, R. C.; Stabilito, I. I.; Wai-si E.; Johnson, R. G. Drug Development Research 1993, 29, 137. The closest prior art is disclosed in U.S. Pat. No. 5,019,562 and WO 93/09790. U.S. Pat. No. 5,019,562 discloses anionic derivatives of cyclodextrins administered concurrently with cortisone for treating pathological conditions associated with undesirable cell or tissue growth. WO 93/09790 discloses antiproliferative polyanionic derivatives of cyclodextrins bearing from 2 to 24 anionic residues per cyclodextrin monomer unit. The present invention differs from all of the above mentioned prior art in that it discloses well defined, modified, polyanionic cyclodextrin derivatives which (a) bear exactly one anionic group per sugar residue at a specific position and (b) are further modified by neutral, lipophilic esters.